Interactions Between the Gastrointestinal Microbiome and Clostridium difficile

Abstract

Antibiotics have significant and long-lasting effects on the intestinal microbiota and consequently reduce colonization resistance against pathogens, including Clostridium difficile. By altering the community structure of the gut microbiome, antibiotics alter the intestinal metabolome, which includes both host- and microbe-derived metabolites. The mechanisms by which antibiotics reduce colonization resistance against C. difficile are unknown yet important for development of preventative and therapeutic approaches against this pathogen. This review focuses on how antibiotics alter the structure of the gut microbiota and how this alters microbial metabolism in the intestine. Interactions between gut microbial products and C. difficile spore germination, growth, and toxin production are discussed. New bacterial therapies to restore changes in bacteria-driven intestinal metabolism following antibiotics will have important applications for treatment and prevention of C. difficile infection.

Keywords: Clostridium difficile; antibiotics; bacterial metabolism; bile acids; colonization resistance; gut microbiota.

Figure 1

Antibiotic-induced alterations in gut microbial metabolism decrease colonization resistance against C. difficile. (a) Bile acids are synthesized from cholesterol by hepatic enzymes. Once synthesized in the gallbladder, primary bile acids (e.g., conjugated, TCA, and unconjugated, CA) travel through the small intestine, where 95% of bile is absorbed in the terminal ileum and through the hepatic system. The small amount of bile acids that reaches the large intestine is further biotransformed by members of the gut microbiota via deconjugation and dehydroxylation into secondary bile acids, including DCA, LCA, and UDCA. C. difficile spores can use primary bile acids TCA and CA in the ileum for germination from a spore to an actively growing vegetative cell. The presence of secondary bile acids and competition from other members of the indigenous gut microbiota are able to inhibit C. difficile outgrowth and colonization in the large intestine. (b) Antibiotic treatment alters the gut microbiota structure, specifically decreasing bacteria that are able to deconjugate and dehydroxylate primary bile acids into secondary bile acids, as shown in the striped red box. The loss of secondary bile acid metabolism and competition from the gut microbiota allow for C. difficile outgrowth, toxin production, and disease. Abbreviations: CA, cholate; DCA, deoxycholate; LCA, lithocholate; TCA, taurocholate; and UDCA, ursodeoxycholate.